Therapeutic composition containing triethylene melamine



Patented Mar. 2, 1 954 THERAPEUTIC COMPOSITION CONTAINING TRIETHYLENEMELAMINE Moses L. Crossley, Plainfield, N. J., assignor to AmericanCyanamid Company,

New York,

N. Y., a corporation of Maine 1 No Drawing. Application March 13, 1951,

Serial No. 215,379

This invention relates to compositions and methods for the treatment ofmalignant growths; particularly lymphomas, (tumors of lymphoid tissue)and leukemias in man and animals.

In the medical field there has existed a need for a composition whichwill differentially cause a destructive action on tumor cells while atthe same time having comparatively little or no effeet on normal cells.In the past, the nitrogen mustards such as N,N-bis(beta-chloroethyl)methylamine have been used in the treatment of lymphomas and certainleukemias. Although effective, N,N-bis(betachloroethyl)methylamine hasnot been very satisfactory because of undesirable and severe sideeffects.

I have now found that triethylene melamine is effective in causingclinical remission and remission of the blood in lymphomas and incertain leukemias. While triethylene melamine has some of thepharmacological actions of nitrogen mustard, it does not cause thesevere side effects. For example, nitrogen mustard produces in patients, acute gastrointestinal upsets and psychic disturbances but theseside reactions are not produced by triethylene melamine when used inproper therapeutic dosage. Furthermore, nitrogen mustard must beadministered intravenously whereas triethylene melamine is effectivewhen administered orally as a tablet, pill or capsule. It may also beadministered parenterally, if desired, with the same diminution in sideeiiects. Triethylene melamine affects adversely a greater number ofmalignant growths than does nitrogen mustard.

It has also been found that triethylene melamine on a weight basis isabout one-half as toxic as nitrogen mustard and that it is about twiceas active. Triethylene melamine is better tolerated by the patient thannitrogen mustard since it possesses a greater spread between the minimumeffective dosage and the maximum tolerated dosage i. e. its efiectivetherapeutic range is much greater.

The optimum single intravenous dosage inhumans appears about 2 to 3 mg.administered twice a week for a course'of two 'weeks; the optimumtherapeutic dosage then being about 8-12 mg. for a two week course oftreatment though dosages as low as 5 mg. and as high as 20 mg. for thetwo week course have been used with good therapeutic effect. The dosagewill vary considerably with'the age of the patient, the condition of thepatient and the progression of his disease. Therefore, singletherapeutic doses may be advisable as low as 0.5 mg. and as high as 6mg.

5 Claims. (01. 16765) of his disease.

. z and the frequency of widely. In smaller animals, suchas the dog, the

single therapeutic dosage will be comparably lower for example, a singletherapeutic dosage may be advisable as low as 0.01 mg.

The optimum single oral dosage in humans appears about 5 mg.administered twice a week for a course of four weeks, the optimumtherapeutic dosage then being about 40, mg. for a four weeks? coursethough doses as 'low as mg. and as high as 100 mg. for a four weekscourse have been used with good therapeutic effects. The oral dosagewill vary considerably with the age of the patient, the condition of thepatient and the progression Therefore, single oral dose may be advisableas low as 1 mg. and as high as 10 mg. and the frequency ofadministration may vary widely. In smaller animals, such as the dog, thesingle therapeutic oral dosage will be comparably lower, for example, asingle oral dosage may be advisable as low as 0.01 mg.

The compound triethylene melamine, known I chemically as 2,4,6tris(ethylenimino)-s-triaon pp. 53.

zine was first described by Pingree and Dahlen Textile FinishingTreatments, PB-1576, published by the Oflice of Technical Services,Department of Commerce, Washington, D. C. It was developed for thecontrol of shrinkage of cellulose materials and. had no knowntherapeutic properties. preparation is described in U. S. P. 2,520,619.

The compound triethylene melamine when used in the treatment of animalssuch as the dog, having lymphomas, showed a marked ability to cause theremission of such lymphomas. When used clinically in the therapy ofcancers of the blood forming tissues in man it was effective in bringingabout the remission of Hodgkin disease for periods of time that varywith diiferent individuals. The compound was also found useful inproducing clinical remission in certain leukemias for periods of timethat vary with different individuals.

The compound of the invention may be dispensed in any of the usualdosage unit forms of pharmaceutical preparations. lets, capsules, pills,solutions, as a powder or in any other desirable form in the therapeuticquantities hereinbefore given. It may be in a dosageunit form for asingle daily therapeutic dose or in smaller units for multiple doses orin larger units for division into single doses. Obviously in addition tothe therapeutic product there may be present excipients, binders,fillers and other therapeutically inert ingredients necessary inadministration may. vary I An improved method for its For example, tab-,

the pharmaceutical preparation. For parenteral administration it may bedissolved in a liquid medium as for example in physiological salinesolution or in a vegetable oil. For example, we may mix 5 to mg. oftriethylene melamine with 95 to 90 mg. of sterile salt in the'dry statein a vial or ampule and the mixture may be dissolved with theappropriate amount of sterile water to produce a freshly preparedsolution for parenteral use as needed.

For oral administration, it maybe compressed without or with otheringredients into tablets or pills or it may be filled into capsules. Acompressed, scored 5 mg. tablet is found convenient for administration.

I claim:

1. A therapeutic composition for the treatment of leukemias andlymphomas in dosage-unit form comprising 0.01 mg. to 10 mg. oftriethylene melamine per dosage unit and a solid pharmaceuticalcarrier.Y

.2. A therapeutic composition for oral administration in the treatmentof .leukemias and lym phomas in dosage-unit form comprising from 0.01mg. to 10 mg. of triethylene melamine per dosage unit and a solidpharmaceutical carrier.

3. A therapeutic composition for intravenous.

administration in the treatment of leukemias and lymphomasin-dosagc-unit form comprising from 0.01 mg. to about 6 mg. oftriethylene melamine References Cited in the file of this patent UNITEDSTATES PATENTS Name Date Wystrach Aug. 29, 1950 OTHER REFERENCES J. A.M. A., vol. 94, No. 23, pages 1864-1865, June 7, 1930.

Geschickter, J. A. M. A., Feb. 1, 1930, vol. 94, No. 5, pages 326-328.

Jacobson et al., J. A.'M'. A, vol. 132, No. 5, Oct. 5, 1946, pages263-271.

Karnofsky, The Merck Report, vol. 60, No. 2, Apr. 1951, pages 4-7.

Number

5. A THERAPEUTIC COMPOSITION IN DOSAGE UNIT FORM FOR THE TREATMENT OFLEUKEMIAS AND LYMPHOMAS COMPRISING FROM ABOUT 0.01 MG. TO 10 MG. OFTRIETHYLENE MELAMINE AND A SIGNIFICANT AMOUNT OF A PHARMACEUTICALCARRIER.